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Cell Signaling

In order to respond to changes in their immediate environment, cells must be able to receive and process signals that originate outside their borders. Individual cells often receive many signals simultaneously, and they then integrate the information they receive into a unified action plan. But cells aren't just targets. They also send out messages to other cells both near and far. Cell signalling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated effectively and, theoretically, artificial tissues may be created.

Unicellular and multicellular organism cell signaling


Cell signaling has been most extensively studied in the context of human diseases and signaling between cells of a single organism. However, cell signaling may also occur between the cells of two different organisms. In many mammals, early embryo cells exchange signals with cells of the uterus. In the human gastrointestinal tract, bacteria exchange signals with each other and with humanepithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.

What Kind of Signals Do Cells Receive?


Most cell signals are chemical in nature. For example, prokaryotic organisms have sensors that detect nutrients and help them navigate toward food sources. In multicellular organisms, growth factors, hormones, neurotransmitters, and extracellular matrix components are some of the many types of chemical signals cells use. These substances can exert their effects locally, or they might travel over long distances. Some cells also respond to mechanical stimuli. For example, sensory cells in the skin respond to the pressure of touch, whereas similar cells in the ear react to the movement of sound waves. In addition, specialized cells in the human vascular system detect changes in blood pressure information that the body uses to maintain a consistent cardiac load.

Types of signals
Cells communicate with each other via direct contact (juxtacrine signaling), over short distances (paracrine signaling), or over large distances and/or scales (endocrine signaling). Some cell-to-cell communication requires direct cellcell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allows for action potential propagation from the cardiac pacemaker region of the heart to spread and coordinately cause contraction of the heart. The Notch signaling mechanism is an example of juxtacrine signaling (also known as contact-dependent signaling) in which two adjacent cells must make physical contact in order to communicate. This requirement for direct contact allows for very precise control of celldifferentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell. Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. Neurotransmitters represent another example of a paracrine signal. Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling. Active species of oxygen and nitric oxide can also act as cellular messengers. This process is dubbed redox signaling.

How Do Cells Recognize Signals?


Cells have proteins called receptors that bind to signaling molecules and initiate a physiological response. Different receptors are specific for different molecules. Dopamine receptors bind dopamine, insulin receptors bind insulin, nerve growth factor receptors bind nerve growth factor, and so on. In fact, there are hundreds of receptor types found in cells, and varying cell types have different populations of receptors.

Receptors can also respond directly to light or pressure, which makes cells sensitive to events in the atmosphere. Receptors are generally transmembrane proteins, which bind to signaling molecules outside the cell and subsequently transmit the signal through a sequence of molecular switches to internal signaling pathways. Membrane receptors fall into three major classes: G-protein-coupled receptors, ion channel receptors, and enzyme-linked receptors. The names of these receptor classes refer to the mechanism by which the receptors transform external signals into internal ones via protein action, ion channel opening, or enzyme activation, respectively. Because membrane receptors interact with both extracellular signals and molecules within the cell, they permit signaling molecules to affect cell function without actually entering the cell. This is important because most signaling molecules are either too big or too charged to cross a cell's plasma membrane. Not all receptors exist on the exterior of the cell. Some exist deep inside the cell, or even in the nucleus. These receptors typically bind to molecules that can pass through the plasma membrane, such as gases like nitrous oxide and steroid hormones like estrogen.

How Do Cells Respond to Signals?


Once a receptor protein receives a signal, it undergoes a conformational change, which in turn launches a series of biochemical reactions within the cell. These intracellular signaling pathways, also called signal transduction cascades, typically amplify the message, producing multiple intracellular signals for every one receptor that is bound. Activation of receptors can trigger the synthesis of small molecules called second messengers, which initiate and coordinate intracellular signaling pathways. For example,cyclic AMP (cAMP) is a common second messenger involved in signal transduction cascades. (In fact, it was the first second messenger ever discovered.) cAMP is synthesized from ATP by the enzyme adenylyl cyclase, which resides in the cell membrane. The activation of adenylyl cyclase can result in the manufacture of hundreds or even thousands of cAMP molecules. These cAMP molecules activate the enzyme protein kinase A (PKA), which then phosphorylates multiple protein substrates by attaching phosphate groups to them. Each step in the cascade further amplifies the initial signal, and the phosphorylation reactions mediate both short- and long-term responses in the cell (Figure 2). How does cAMP stop signaling? It is degraded by the enzyme phosphodiesterase. Other examples of second messengers include diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), which are both produced by the enzyme phospholipase, also a membrane protein. IP3 causes the release of Ca2+ yet another second messenger from intracellular stores. Together, DAG and Ca2+ activate another enzyme called protein kinase C (PKC).

How Do Signals Affect Cell Function?


Protein kinases such as PKA and PKC catalyze the transfer of phosphate groups from ATP molecules to protein molecules. Within proteins, the amino acids serine, threonine, and tyrosine are especially common sites for phosphorylation. These phosphorylation reactions control the activity of many enzymes involved in intracellular signaling pathways. Specifically, the addition of phosphate groups causes a conformational change in the enzymes, which can either activate or inhibit the enzyme activity. Then, when appropriate, protein phosphatases remove the phosphate groups from the enzymes, thereby reversing the effect on enzymatic activity. Phosphorylation allows for intricate control of protein function. Phosphate groups can be added to multiple sites in a single protein, and a single protein may in turn be the substrate for multiple kinases and phosphatases. At any one time, a cell is receiving and responding to numerous signals, and multiple signal transduction pathways are operating in its cytoplasm. Many points of intersection exist among these pathways. For instance, a single second messenger or protein kinase might play a role in more than one pathway. Through this network of signaling pathways, the cell is constantly integrating all the information it receives from its external environment.

Signaling pathways
In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway. In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. Activation of Notch can cause the Notch protein to be altered by a protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. This pathway involves changes of protein-protein interactions inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. Complex multi-component signal transduction pathways provide

opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.

Steroid Receptors
Steroids are small hydrophobic molecules that can freely diffuse across the plasma membrane, through the cytosol, and into the nucleus.

Receptors
Steroid receptors are homodimers of zinc-finger proteins that reside within the nucleus (except for the glucocorticoid receptor which resides in the cytosol until it binds its ligand). Until their ligand finds them, some steroid receptors within the nucleus associate with histone deacetylases (HDACs), keeping gene expression repressed in those regions of the chromosome.

Ligands
Some steroids that regulate gene expression:

glucocorticoids (e.g., cortisol) mineralocorticoids (e.g., aldosterone) sex hormones such as


estradiol progesterone testosterone

ecdysone

Mechanism

The steroid binds its receptor. The complex releases the HDACs and recruits histone acetylases (HATs) relieving chromosome repression; binds to a specific DNA sequence the Steroid Response Element (SRE) in the promoters of genes it will turn on.

Nitric Oxide (NO) Receptors


NO diffuses freely across cell membranes. There are so many other molecules with which it can interact, that it is quickly consumed close to where it is synthesized. Thus NO acts in a paracrine or even autocrine fashion affecting only cells near its point of synthesis.

Receptors
The signaling functions of NO begin with its binding to protein receptors in the cell. The binding sites can be either:

a metal ion in the protein or one of its S atoms (e.g., on cysteine).

Mechanism
In either case, binding triggers an allosteric change in the protein which, in turn, triggers the formation of a "second messenger" within the cell. The most common protein target for NO seems to be guanylyl cyclase, the enzyme that generates the second messenger cyclic GMP (cGMP).

G-Protein-Coupled Receptors (GPCRs)


Receptors
These are transmembrane proteins that wind 7 times back and forth through the plasma membrane. Humans have over 800 different GPCRs.

Their ligand-binding site is exposed outside the surface of the cell. Their effector site extends into the cytosol.

Ligands
Some of the many ligands that alter gene expression by binding GPCRs:

protein and peptide hormones such as:


thyroid-stimulating hormone (TSH) ACTH

Serotonin and GABA (which affect gene expression in addition to their role as neurotransmitters)

Mechanism
The ligand binds to a site on the extracellular portion of the receptor.Binding of the ligand to the receptor

activates a G protein associated with the cytoplasmic C-terminal. This initiates the production of a "second messenger". The most common of these are:
cyclic AMP, (cAMP) which is produced by adenylyl

cyclase from ATP


inositol 1,4,5-trisphosphate (IP3)

The second messenger, in turn, initiates a series of intracellular events (shown here as short arrows) such as: phosphorylation and activation of enzymes
release of Ca2+ into the cytosol from stores within the endoplasmic

reticulum

In the case of cAMP, these enzymatic changes activate the transcription factor CREB (cAMP response element binding protein) Bound to its response element 5' TGACGTCA 3'

in the promoters of genes that are able to respond to the ligand, activated CREB turns on gene transcription. The cell begins to produce the appropriate gene products in response to the signal it had received at its surface.

In addition to their roles in affecting gene expression, GPCRs regulate many immediate effects within the cell that do not involve gene expression.

Turning GPCRs Off


A cell must also be able to stop responding to a signal. Several mechanisms cooperate in turning GPCRs off.

When activated, the G subunit of the G protein swaps GDP for GTP. However, the G subunit is a GTPase and quickly converts GTP back to GDP restoring the inactive state of the receptor. [Link to a discussion.] The receptor itself is phosphorylated by a kinase, which not only reduces the ability of the receptor to respond to its ligand but recruits a protein, -arrestin, which further desensitizes the receptor, and triggers the breakdown of the second messengers of the GPCRs:

cAMP for some GPCRs DAG for others.

Frizzled Receptors and Wnt Signaling


Receptors
Frizzled receptors, like GPCRs, are transmembrane proteins that wind 7 times back and forth through the plasma membrane.

Their ligand-binding site is exposed outside the surface of the cell. Their effector site extends into the cytosol.

Ligands

Their ligands are Wnt proteins. These get their name from two of the first to be discovered, proteins encoded by wingless (wg) in Drosophila and its homolog Int-1 in mice.

The roles of -catenin


-catenin molecules connect actin filaments to the cadherins that make up adherens junctions that bind cells together. Any excess -catenin is quickly destroyed by a multiprotein degradation complex. (One component is the protein encoded by the APCtumor suppressor gene.) The degradation complex

phosphorylates -catenin so it can have ubiquitin molecules attached to prepare it for destruction in proteasomes.

But undegraded -catenin takes on a second function: it becomes a potent transcription factor.

Mechanism

The binding of a Wnt ligand to Frizzled (done with the aid of cofactors) activates Frizzled. This, in turn, activates a cytosolic protein called Dishevelled. Activated Dishevelled inhibits the -catenin degradation complex so -catenin escapes destruction by proteasomes and is free to enter the nucleus where it binds to the promoters and/or enhancers of its target genes.

Wnt-controlled gene expression plays many roles:


in embryonic development (e.g., a gradient from low at the future head to high at the future tail establishes the anterior-posterior axis throughout the metazoa); it guides regeneration as well as regulating activities in the adult body.

The Hedgehog Signaling Pathway


Receptor
Patched (Ptc) a 12-pass transmembrane protein embedded in the plasma membrane.

Ligands
Secreted hedgehog proteins (Hh) that diffuse to their targets. Mammals have three hedgehog genes encoding three different proteins. However, hedgehog was first identified in Drosophila, and the bristly phenotype produced by mutations in the gene gave rise to the name.

Mechanism

In mammals, when there is no hedgehog protein present, the patched receptors bind a second transmembrane protein called smoothened (Smo). However, when Hh protein binds to patched, the Smo protein separates from Ptc enabling Smo to activate a zinc-finger transcription factor designated GLI. GLI migrates into the nucleus when it activates a variety of target genes.

Hedgehog signaling plays many important developmental roles in the animal kingdom. For example,

wing development in Drosophila; development of the brain, GI tract, fingers and toes in mammals; regeneration in planarians

Mutations or other sorts of regulatory errors in the hedgehog pathway are associated with a number of birth defects as well as some cancers. Basal-cell carcinoma, the most common skin cancer (and, in fact, the most common of all cancers in much of the world), usually has mutations causing

extra-high hedgehog or suppressed patched activity (both leading to elevated GLI activity).

The Notch Signaling Pathway


This pathway is found throughout the animal kingdom. It differs from many of the other signaling pathways discussed here in that the ligands as well as their receptors are transmembrane proteins embedded in the plasma membrane of cells. Thus, signaling in this pathway requires direct cell-to-cell contact.

Receptors
Notch proteins are single-pass transmembrane glycoproteins. They are encoded by four genes in vertebrates. However, the first notch gene was discovered in Drosophila where its mutation produced notches in the wings.

Ligands
Their ligands are also single-pass transmembrane proteins. There are many of them and often several versions within a family (such as the serrate and delta protein families).

Mechanism
When a cell bearing the ligand comes in contact with a cell displaying the notch receptor, the external portion of notch is cleaved away from the cell surface (and engulfed by the ligand-bearing cell byendocytosis). The internal portion of the notch receptor is cut away from the interior of the plasma membrane and travels into the nucleus where it activates transcription factors that turn the appropriate genes on (and off). It would appear that proper development of virtually all organs (e.g., brain, immune system, pancreas, GI tract, heart, blood vessels, mammary glands) depends on notch signaling. Notch signaling appears to be a mechanism by which one cell tells an adjacent cell which path of differentiation to take (or not take). Defects in notch signaling have been implicated in some cancers, e.g. melanoma.

Cytokine Receptors
Dozens of cytokine receptors have been discovered. Most of these fall into one or the other of two major families: 1. Receptor Tyrosine Kinases (RTKs) and 2. Receptors that trigger a JAK-STAT pathway.

1. Receptor Tyrosine Kinases (RTKs)


Receptors
The receptors are transmembrane proteins that span the plasma membrane just once. 58 different RTKs are found in humans.

Ligands
Some ligands that trigger RTKs:

Insulin Insulin-like Growth Factor-1 (IGF-1) Vascular Endothelial Growth Factor (VEGF) Platelet-Derived Growth Factor (PDGF) Epidermal Growth Factor (EGF) Fibroblast Growth Factors (FGFs). (A mutation in one of their receptors causes achondroplasia the most common type of dwarfism.)

Mechanism

Binding of the ligand to two adjacent receptors forms an active homodimer. This activated dimer is a tyrosine kinase; an enzyme that attaches phosphate groups to certain tyrosine (Tyr) residues first on itself, then on other proteins converting them into an active state. Many of these other proteins are also tyrosine kinases (the human genome encodes 90 different tyrosine kinases) and in this way a cascade of expanding phosphorylations occurs within the cytosol.

Some of these cytosolic tyrosine kinases act directly on gene transcription by entering the nucleus and transferring their phosphate to transcription factors thus activating them. Example: The cytosol of B cells contains Btk ("Bruton's tyrosine kinase") which is essential to turning on appropriate gene expression when a B cell encounters antigen. Inherited mutations in the gene encoding Btk cause X-linked agammaglobulinemia in boys. These boys cannot manufacture antibodies and suffer recurrent bacterial infections unless given periodic injections of immune globulin (IG).

Others act indirectly through the production of second messengers.

Turning RTKs Off


A cell must also be able to stop responding to a signal. For growth factor receptors, failure to do so could lead to uncontrolled mitosis = cancer. For the RTKs, this is done by quickly engulfing and destroying the ligandreceptor complex by receptor-mediated endocytosis. Proto-Oncogenes One might expect that anything which leads to the inappropriate expression of receptors that trigger cell division could lead to cancer (uncontrolled cell division). And, in fact,

The gene encoding PDGF is SIS; it is a proto-oncogene, and mutated versions participate in making the cell cancerous. The genes encoding receptors for EGF are also proto-oncogenes and are expressed at abnormally high levels in several human cancers. Two monoclonal antibodies that target these receptors trastuzumab (Herceptin) that inactivates HER2 ("Human Epidermal growth factor Receptor 2") and cetuximab (Erbitux) that inactivates HER1.

show promise against breast cancer.

Two tyrosine kinase inhibitors


gefitinib (Iressa) and erlotinib (Tarceva)

block the action of the EGF receptors on the cells of certain lung cancers and have shown some promise against these cancers. Mutant versions of some of the "second-order" kinases are also associated with cancer:

The oncogene SRC encodes a mutated version of a normal tyrosine kinase associated with the inner face of the plasma membrane. The fusion protein BCR/ABL produced by the Philadelphia chromosome activates constitutively (all the time) the cytosolic tyrosine kinase ABL that normally would be activated only when the cell is stimulated by a growth factor (e.g., PDGF). The result: chronic myelogenous leukemia (CML). A promising treatment: Imatinib mesylate (Gleevec also known STI571). This molecule fits into the active site of the ABL protein preventing ATP from binding there. Without ATP as a phosphate donor, the ABL protein cannot phosphorylate its substrate(s). RAF. This kinase participates in a signaling pathway that links RTKs to gene activation. Binding of a ligand to the RTK activates an intracellular molecule called RAS, which then activates RAF. In mammals, this pathway promotes mitosis. Excessive activity of the RAS gene or mutations in RAS and/or RAF are associated with many types of cancer so RAS and RAF are proto-oncogenes.

15% of all human tumors contain a mutated RAF, and 66% of melanomas a highly-malignant skin cancer of melanocytes contain a mutated RAF (called BRAF).

2. JAK-STAT Pathways
Receptors
These consist of 2 identical single-pass transmembrane proteins (i.e., homodimers) embedded in the plasma membrane. Each of their cytoplasmic ends binds a molecule of a Janus kinase ("JAK").

Ligands
Many ligands trigger JAK-STAT pathways:

Interferons Most of the interleukins, e.g.,


IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-11, IL-12, IL-13

Growth hormone (GH) Leptin Prolactin (PRL) Erythropoietin (EPO) Thrombopoietin Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

Mechanism

Binding of the ligand activates the JAK molecules which phosphorylate certain tyrosine (Tyr) residues on each other as well as on one or another of several STAT ("Signal Transducer and Activator of Transcription) proteins. These, in turn, form dimers which enter the nucleus and bind to specific DNA sequences in the promoters of genes that begin transcription.

The JAK-STAT pathways are much shorter and simpler than the pathways triggered by RTKs, and so the response of cells to these ligands tends to be much more rapid.

Transforming Growth Factor-beta (TGF-) Receptors


Receptors
Two types of single-pass transmembrane proteins that, when they bind their ligand, become kinases that attach phosphate groups to serine and/or threonine residues of their target proteins.

Ligands
Ligands for these receptors include:

Transforming Growth Factor-beta (hence the name) activins Nodal Bone Morphogenic Proteins (BMPs) myostatin, an inhibitor of skeletal muscle growth.

Mechanism

The ligand binds to the extracellular portion of the receptors, which then phosphorylate one or more SMAD proteins in the cytosol. SMAD proteins get their name from the TGF-/BMP homologs found in C. elegans ("Sma") and Drosophila ("Mothers Against Decapentaplegic"). The SMAD proteins move into the nucleus where they form heterodimers with another SMAD protein designated SMAD4. These dimers bind to a DNA sequence (CAGAC) in the promoters of target genes and with the aid of other transcription factors enhance, or repress, as the case may be, gene transcription.

Tumor-Suppressor Genes
The TGF- signaling pathway suppresses the cell cycle in several ways. So it is not surprising that defects in the pathway are associated with cancer. Mutations in the genes encoding

the TGF- receptors as well as of the SMAD proteins

are found in many cancers including pancreatic and colon cancer. Thus all these genes qualify as tumor-suppressor genes.

Tumor Necrosis Factor-alpha (TNF-) Receptors and the NF-B Pathway


TNF- is made by macrophages and other cells of the immune system.

Receptors
Trimers of 3 identical cell-surface transmembrane proteins.

Ligands

TNF- (hence the name) Lymphotoxin (LT; also known as TNF-)

Mechanism

NF-B resides in the cytosol bound to an inhibitor called IB. Binding of ligand to the receptor triggers phosphorylation of IB IB then becomes ubiquinated and destroyed by proteasomes. This liberates NF-B so that it is now free to move into the nucleus where it acts as a transcription factor binding to the promoters and/or enhancers of more than 60 genes:
NF-B got its name from its discovery as a transcription factor bound to

the enhancer of the kappa light chain antibody gene.


However, it also turns on the genes encoding IL-1 and other cytokines that

promote inflammation. The immunosuppressive and anti-inflammatory effects of glucocorticoids are caused by their enhancing the production of IB.
NF-B also turns on genes needed for cell proliferation,

and angiogenesis.

cell adhesion,

The T-Cell Receptor for Antigen (TCR)

T cells use a transmembrane dimeric protein as a receptor for a particular combination of an antigen fragment nestled in the cleft of a histocompatibility molecule.

Mechanism
Activation of the TCR (when aided by costimulator molecules also present in the plasma membrane

causes a rise in intracellular Ca2+ which activates calcineurin, a phosphatase which removes phosphate from NF-AT ("Nuclear Factor of Activated T cells"). Dephosphorylated NF-AT enters the nucleus, and with the help of accessory transcription factors (designated AP-1), binds to the promoters of some 100 genes expressed in activated T cells.

The immunosuppressant drugs tacrolimus and cyclosporine inhibit calcineurin thus reducing the threat of transplant rejection by T cells. Activation of the TCR, when accompanied by an as-yet-unidentified second signal, causes NF-AT to associate with a different transcription factor (designated Foxp3). Instead of activating the T cell, this turns on genes that convert the cell into a suppressive regulatory T cell (Treg) instead

Conclusion
Cells typically receive signals in chemical form via various signaling molecules. When a signaling molecule joins with an appropriate receptor on a cell surface, this binding triggers a chain of events that not only carries the signal to the cell interior, but amplifies it as well. Cells can also send signaling molecules to other cells. Some of these chemical signals including neurotransmitters travel only a short distance, but others must go much farther to reach their targets.

The signaling systems discussed here are only some of the major players, and even the description of these is greatly oversimplified because many of these signaling pathways interconnect with one another (creating "cross talk"). While cross talk might seem to create problems (for our comprehension as well as for the cell!), in fact it is probably essential to precisely modulate the genetic response to a variety of ligands reaching the cell at the same time and in varying intensities.